Lyme disease is the most common vector-borne disease in the United State. The causative agent Borrelia burgdorferi (Bb) is maintained through a complex enzootic cycle involving in tick and mammalian hosts. Consequently, the spirochete has to adapt to and survive in these two dramatically different hosts. After being deposited in the skin, the spirochetes then disseminate through the skin into the blood and colonize other organs and cause numerous clinical symptoms that commonly involve the skin, joints, heart and nervous system. In the United States, one of the major manifestations of the disease is Lyme arthritis. The most intriguing feature of Bb is that this spirochete can preferentially express selected genes in the different hosts, at different times, and even in different microenvironments during its life cycle and the disease development. This ability is not only critical for the spirochete to adapt to and thrive in the different hosts but also plays very important roles in the spirochete pathogenesis. Clearly, Bb developed complex regulatory systems to sense environmental changes and correspondingly manipulate such genetic adaptation. However, only a few regulatory systems have been identified in Bb. Two-component systems are the most common signaling transduction pathways in the response of bacteria to both external and internal signals. Several cellular processes are regulated by two-component systems, including virulence gene control, host-adaptations, sporulation, osmoregulation and chemotaxis. In this proposal, we hypothesize that a bacterial two-component system HK1-RR1 plays very important roles in the pathogenesis of Bb in terms of gene regulation, mammalian infection and vector transmission. Such hypotheses will be tested by several approaches, including biochemical, genetic, genomic and proteomic assays as well as a mouse model of Lyme disease and mouse-tick infection studies. The obtained data from this project will help us to understand how Bb regulates its genetic adaptation during its life cycle and the roles of such genetic adaptation in the mammalian infection and vector transmission. The results may lead to new means of disease prevention and treatment. Lyme disease is the most common tick-borne disease in the United States, which is caused by the spirochete Borrelia burgdorferi. Host adaptation plays very important roles in the disease. The goal of this project is to investigate how the spirochete regulates host adaptation through a bacterial two- component signaling pathway and its role in the spirochete pathogenesis. The obtained results may lead to new means of disease prevention and treatment.